1-(2-[4-(6-methoxy-3,4-dihydronaphthalene-1-yl)phenoxy]ethyl)pyrrolidine, as shown below,
is a key intermediate in the preparation of lasofoxifene and its salts. Lasofoxifene D-tartrate, (−)-(5R,6S)-6-Phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-5,6,7,8tetrahydronaphthalen-2-ol D tartrate, represented by the structural formula,
is an estrogen agonist. FABLYN® (lasofoxifene) functions as selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in post-menopausal women at increased risk of fracture and has received approval from the European Commission (EC). FABLYN® was submitted for approval in Europe in January 2008.
Lasofoxifene is disclosed in U.S. Pat. No. RE39,558 while its tartrate salt is disclosed in U.S. Pat. Nos. 5,948,809. RE39,558 describes a process of preparing 1-(2-[4-(6-Methoxy-3,4-dihydronaphthalene-1-yl)phenoxy]ethyl)pyrrolidine, which is obtained as an oil, by the reaction of 1-[2-(4-bromophenoxy)ethyl)]pyrrolidine and 6-methoxy-1-tetralone with butyl lithium (BuLi) in tetrahydrofuran (THF) and in the presence of cesium chloride.
Polymorphic forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in, for example, different thermodynamic properties and stabilities specific to the particular polymorph form. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks.
When a compound is in its solid form, it allows ease of handling particularly when said compound participates in a multiple step synthesis. Herein, the preparation and isolation of 1-(2-[4-(6-methoxy-3,4-dihydronaphthalene-1-yl)phenoxy]ethyl)pyrrolidine in its solid and crystalline state subsequently contributes to the facile synthesis of lasofoxifene.